At least 5% of individuals with hypertension have adrenal aldosterone-producing adenomas (APAs). Gain-of-function mutations in KCNJ5 and apparent loss-of-function mutations in ATP1A1 and ATP2A3 were reported to occur in APAs1,2. We find that KCNJ5 mutations are common in APAs resembling cortisol-secreting cells of the adrenal zona fasciculata but are absent in a subset of APAs resembling the aldosterone-secreting cells of the adrenal zona glomerulosa3. We performed exome sequencing of ten zona glomerulosa–like APAs and identified nine with somatic mutations in either ATP1A1, encoding the Na+/K+ ATPase α1 subunit, or CACNA1D, encoding Cav1.3. The ATP1A1 mutations all caused inward leak currents under physiological conditions, and the CACNA1D mutations induced a shift of voltage-dependent gating to more negative voltages, suppressed inactivation or increased currents. Many APAs with these mutations were <1 cm in diameter and had been overlooked on conventional adrenal imaging. Recognition of the distinct genotype and phenotype for this subset of APAs could facilitate diagnosis.
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Cambridge, UK. We are grateful to M. Gurnell for discussion and care of many of the patients, to N. Jamieson for all the laparoscopic adrenalectomies and to A. Marker for pathological diagnosis. We thank Dr. Yasmin for providing peripheral DNA samples from healthy, normotensive subjects. We thank R. Kuc and the Human Research Tissue Bank of Addenbrooke's Hospital, which is supported by the NIHR Cambridge BRC, for help with storage of fresh adrenal tissue for the Cambridge cohort; we particularly acknowledge B. Haynes, D. Walters, K. Brown, M. Elazoui, C. Karpinskyj, M. Bromwich and K. Payne. The work was funded by the British Heart Foundation (PG/07/085/23349), the Wellcome Trust (085686/Z/08/A), the NIHR Cambridge Biomedical Research Centre (Cardiovascular) and an NIHR Senior Investigator award to M.J.B. The work was also supported by the Austin Doyle Award funded by Servier Australia (to E.A.B.A.). C.A.B. is supported by the Wellcome Trust PhD program in Metabolic and Cardiovascular Disease. J.Z. is supported by the Cambridge Overseas Trust and the Sun Hung Kai Properties–Kwoks' Foundation PhD program. G.S.H.Y. was supported by European Union FP7-HEALTH-2009-241592 EurOCHIP and FP7-FOOD-266408 Full4Health. Aarhus, Denmark. We thank J. Egebjerg Jensen for discussion of the electrophysiology data. H.P. was supported by grants from The Carlsberg Foundation, The Lundbeck Foundation and L'Oréal/UNESCO. University of Innsbruck, Austria. The work was supported by the Austrian Science Fund (F44020). University College London, UK. We thank W. Pratt for technical assistance. The work was supported by the Wellcome Trust (098360/Z/12/Z). Hradec Kralove, Czech Republic. We thank A. Ryska, who selected the most appropriate adrenal samples for the Czech cohort. Funding is provided by program PRVOUK P037/03. Nijmegen, The Netherlands. We thank J.W.M. Lenders for introducing the collaboration and for his leading role in the recruitment of the Dutch cohort.
Supplementary Figures 1–8 and Supplementary Tables 1–4
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Biophysical Journal (2019)